Cervical cancer is the most common form of cancer in developing countries and the second most common cancer worldwide. Epidemiologically, human papillomaviruses (HPV) and adeno-associated viruses (AAV) are inversely associated with cervical cancer, with HPV "causing" (reviews 1-5) and AAV protecting against (6-14) this cancer. Our long-range goal is to understand the relationship and interactions between HPV and AAV and its impact on the process of cervical carcinogenesis. In seeking this goal, our first objective will be to investigate the mechanisms whereby HPV can support AAV productive replication, and how AAV negatively influences the natural history of HPV. The central hypothesis of this application is that AAV can interact in a complex manner, with both positive and negative aspects, on HPV s phenotypes (including DNA replication, transcription and oncogenesis), but that HPV gene expression is required for AAV productive replication and gene expression. Preliminary data presented here are fully consistent with this hypothesized bi-directional interaction. Their laboratories are well prepared to pursue the proposed specific aims as indicated by our publication records. Specifically we propose to: Aim #1: Determine if HPV can serve as a helper for AAV in a productive organotypic culture system ( raft ) for HPV, identifying the HPV genes responsible for the effect. Aim #2: Determine the affect of AAV infection on the HPV life cycle including: HPV DNA replication, HPV virion synthesis, HPV transcription, and host cell differentiation. HPV is a wide-spread sexually transmitted pathogen. The study of the AAV-HPV interaction is strongly needed because of likely alterations in HPVs pathogenesis in the presence of AAV. Furthermore, AAV-helper virus interactions are poorly understood. The AAV-HPV interaction provides a superior, simpler system for such studies. We expect to describe in an HPV helper virus system the kinetics and magnitude of AAV productive replication, and define the HPV genes responsible for this helper function. Furthermore, we expect to define the AAV MOI dependent effects on HPV s vegetative cycle and on the host tissue s differentiation program.